4-Phenlthiazole and 4-phenylimidizole derivatives and their use as medicaments for the treatment of neurodegenerative diseases, pain and epilepsy

ABSTRACT

The invention relates to novel derivatives of 4-phenylthiazoles and 4-phenylimidazoles and the use thereof medicament. The invention especially relates to the following compounds: butyl-2-[4-(4-(aminophenyl)-1&lt;i&gt;H&lt;/i&gt;-imidazol-2-yl]ethyl-carbamate, and 4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol, and the salts of the same.

The present invention relates to new 4-phenylthiazole and4-phenylimidazole derivatives and their use as medicaments. Saidmedicaments are intended to inhibit monoamine oxydases (MAO) and/orlipidic peroxidation and/or to act as modulators of the sodium channels.

The compounds of the invention often present 2 or 3 of the activitiesmentioned above, which confer advantageous pharmacological properties onthem.

In fact, taking into account the potential role of the MAO's and ROS's(“reactive oxygen species”, at the origin of lipidic peroxidation) inphysiopathology, the new derivatives of the present invention canproduce beneficial or favourable effects in the treatment of pathologieswhere these enzymes and/or these radicular species are involved. Inparticular:

-   -   disorders of the central or peripheral nervous system such as        for example neurological diseases where Parkinson's disease,        cerebral or spinal cord traumatisms, cerebral infarction, sub        arachnoid hemorrhage, epilepsy, ageing, senile dementia,        Alzheimer's disease, Huntington's chorea, amyotrophic lateral        sclerosis, peripheral neuropathies, pain can in particular be        mentioned;    -   schizophrenia, depressions, psychoses;    -   memory and mood disorders;    -   pathologies such as for example migraine;    -   behavioural disorders, bulimia and anorexia;    -   auto-immune and viral diseases such as for example lupus, AIDS,        parasitic and viral infections, diabetes and its complications,        multiple sclerosis.    -   addiction to toxic substances;    -   proliferative and inflammatory pathologies;    -   and more generally all the pathologies characterized by an        excessive production of ROS's and/or participation of MAO's.

In all of these pathologies, experimental evidence exists whichdemonstrates the involvement of ROS's (Free Radic. Biol. Med. (1996) 20,675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of SyntheticAntioxidants), 1-52) as well as the involvement of MAO's (Goodman &Gilman's: The pharmacological basis of therapeutics, 9th ed., 1995,431-519).

The benefit of a combination of the inhibitory activities of MAO andinhibition of lipidic peroxidation is for example well illustrated inParkinson's disease. This pathology is characterized by a loss ofdopaminergic neurons of the nigrostriatal route the cause of which wouldin part be linked to an oxidizing stress due to ROS's. The exogenicdopamine from L Dopa is used in therapeutics in order to maintainsufficient levels of dopamine. MAO inhibitors are also used with L Dopato avoid its metabolic degradation but do not act on the ROS's.Compounds which act both on MAO's and ROS's will therefore have acertain advantage.

Moreover, the character of the modulator of the sodium channels is veryuseful for therapeutic indications such as:

-   -   the treatment or prevention of pain, and in particular:        -   post-operative pain,        -   migraine,        -   neuropathic pain such as trigeminal neuralgia, post-herpetic            pain, diabetic neuropathies, glossopharyngeal neuralgias,            secondary radiculopathies and neuropathies associated with            metastatic infiltrations, adiposis dolorosa and pain            associated with burns,        -   central pain as a result of vascular cerebral accidents,            thalamic lesions and multiple sclerosis, and        -   chronic inflammatory pain or pain linked to a cancer;    -   the treatment of epilepsy;    -   the treatment of disorders linked to neurodegeneration, and in        particular:        -   vascular cerebral accidents,        -   cerebral traumatism, and        -   neurodegenerative diseases such as Alzheimer's disease,            Parkinson's disease and amyotrophic lateral sclerosis;    -   the treatment of bipolar disorders and irritable bowel syndrome.

The concrete advantages of the presence in a compound of at least one ofthese activities is therefore clearly apparent from the above.

The European Patent Application EP 432 740 describes derivatives ofhydroxyphenylthiazoles, which can be used in the treatment ofinflammatory diseases, in particular rheumatic diseases. Thesederivatives of hydroxyphenylthiazoles show properties of trapping freeradicals and inhibitors of the metabolism of arachidonic acid (theyinhibit lipoxygenase and cyclooxygenase).

Other derivatives of hydroxyphenylthiazoles or hydroxyphenyloxazoles aredescribed in the PCT Patent Application WO 99/09829. These haveanalgesic properties.

A certain number of derivatives of 4-phenylimidazole have moreover beendescribed by the Applicant in the PCT Patent Application WO 99/64401 asagonists or antagonists of somatostatin. However, said derivatives ofimidazoles have therapeutic properties in fields different from thoseindicated above (suppression of the growth hormone and the treatment ofacromegalia, treatment of the recurrence of stenosis, inhibition of thesecretion of gastric acid and prevention of gastro-intestinal bleedingin particular).

Moreover, the compounds of general formula (A1)

in which

-   R1 represents one of the aryl, heteroaryl, aralkyl or cycloalkyl    radicals optionally substituted by one to three substituents chosen    independently from a halogen atom, the CF₃, CN, OH, alkyl or alkoxy    radical, SO₂R9 with R9 representing NH₂ or NHCH₃;-   X represents NR2, R2 representing H or alkyl;-   Y represents N or CR3;-   Z represents CR3 or N;-   on the condition however that Y and Z are not both CR3 or N at the    same time;-   R3 represents H, alkyl, halogen, hydroxyalkyl or phenyl optionally    substituted by 1 to 3 substituents chosen from H, CF₃, CN, SO₂NH₂,    OH, alkyl or alkoxy;-   m represents 0, 1 or 2;-   R4 represents H or alkyl;-   when Z represents CR3, then R3 and R4 can also represent together    —(CH₂)_(n1)— with n1 an integer from 2 to 4 or R2 and R4 can also    represent together —(CH₂)_(n2)— with n2 an integer from 2 to 4;-   R5 and R6 represent independently H, alkyl, alkoxy, aryl or aralkyl;-   NR5R6 can also represent together (in particular):    -   the optionally substituted 2-(1,2,3,4-tetrahydroquinolyl)        radical,    -   a radical        in which R7 represents one of the phenyl, benzyl or phenethyl        radicals in which the phenyl ring can be substituted;    -   a radical        in which p is an integer from 1 to 3,-   W is N and R8 represents H, CF₃, one of the phenyl, pyridyl or    pyrimidinyl radicals optionally substituted once to twice by    radicals chosen from halogen, OH, alkyl or alkoxy, or-   W is CH and R8 represents phenyl optionally substituted or aralkyl    optionally substituted on the aryl group;

have been described in the PCT Patent Application WO 96/16040 as partialagonists or antagonists of the dopamine sub-receptors of the brain or asprodrug forms of such partial agonists or antagonists. Therefore thesecompounds would have useful properties in the diagnosis and treatment ofaffective disorders such as schizophrenia and depression as well ascertain disorders of movement such as Parkinson's disease.

It has also been described in the PCT Patent Application WO 98/27108that certain amides of general formula (A2)

in which:

-   R1 represents in particular an alkyl, optionally substituted phenyl    or optionally substituted heterocyclic aryl radical;-   R2 represents H or phenylalkyl;-   R4 represents H, quinolyl, 3-4-methylenedioxyphenyl or one of the    phenyl or pyridyl radicals optionally substituted by a radical or    radicals chosen in particular from alkyl, alkoxy, alkylthio,    optionally protected hydroxy, amino, alkylamino, dialkylamino;-   R5 represents H or an imidazolyl, phenyl, nitrophenyl, phenylalkyl    radical, or also a —CO—N(R7)(R8) radical, in which R7 and R8    represent independently H, phenyl, phenylalkyl, alkyl or alkoxy;-   or R4 and R5 in combination form a group of formula —CH═CH —CH═CH—;-   Y is a phenylene radical substituted by a phenyl, phenoxy or    phenylalkoxy radical, or a group of formula —CH(R3)—, in which R3    represents H or a radical of formula —(CH₂)_(n)— R6, in which R6    represents an optionally protected hydroxy, acyl, carboxy,    acylamino, alkoxy, phenylalkoxy, alkylthio, optionally substituted    phenyl, optionally substituted pyridyl, pyrazinyl, pyrimidinyl,    furyl, imidazolyl, naphthyl, N-alkylindolyl or    3,4-methylenedioxyphenyl radical and n is an integer from 0 to 3;-   R2 and R3 taken together with the carbon atoms which carry them can    form a phenyl group;-   X represents S or NR9;-   R9 representing H, an alkyl or cycloalkyl radical, or also a benzyl    radical optionally substituted once on its phenyl part by H, alkyl    or alkoxy;    are inhibitors of the NO synthases and can be used to treat diseases    which include in particular cardiovascular or cerebral ischemia,    cerebral hemorrhage, disorders of the central nervous system,    Alzheimer's disease, multiple sclerosis, diabetes, hepatitis,    migraine, rheumatoid arthritis and osteoporosis.

The Applicant has also described in the PCT Patent Application WO01/26656 a family of compounds comprising derivatives of4-phenylthiazole and 4-phenylimidazole. The compounds of this familyinhibit monoamine oxydases (MAO) and/or lipidic peroxidation and/or actas modulators of the sodium channels.

The Applicant has now unexpectedly discovered that certain particularcompounds belonging to the family described in the PCT PatentApplication WO 01/26656, namely the compounds described in the examplesof the present application, possess particularly advantageous propertiescompared to their closest homologues of the PCT Patent Application WO01/26656.

These advantageous properties make these compounds particularly suitablefor a use in the treatment of neurodegenerative diseases, and inparticular those indicated previously, pain (particularly pain ofneuropathic origin) or epilepsy.

The invention therefore relates to the use of one of the followingcompounds:

-   butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;-   N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;-   [4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;-   2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;-   N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;-   N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;-   2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;-   4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   (1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;-   4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;-   4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;    or a pharmaceutically acceptable salt of one of the latter;

for preparing a medicament intended to inhibit monoamine oxydases (MAO)and/or lipidic peroxidation and/or to act as modulators of the sodiumchannels.

The invention also relates to the use of one of the abovementionedcompounds or pharmaceutically acceptable salts for preparing amedicament intended to treat disorders/pathologies chosen fromneurodegenerative diseases, pain (particularly pain of neuropathicorigin) and epilepsy.

Preferably, the neurodegenerative diseases intended to be treated by amedicament prepared according to the invention will be chosen fromParkinson's disease, Alzheimer's disease, Huntington's chorea andamyotrophic lateral sclerosis.

According to a first variant of the invention, the compounds of Examples2 to 28 (sometimes described in the form of salts) or theirpharmaceutically acceptable salts are preferred when an inhibitoryactivity on MAO's and/or the ROS's is sought in the first place. Morepreferentially, the compounds of Examples 6, 7, 10, 15 to 17, 22 and 28(described in the form of hydrochloride salts), or theirpharmaceutically acceptable salts, will be used for preparing amedicament according to the invention when an inhibitory activity onMAO's and/or the ROS's is sought in the first place. Even morepreferentially, the compound of Example 28 (described in the form of itshydrochloride salt), or its pharmaceutically acceptable salts, will beused for preparing a medicament according to the invention when aninhibitory activity on MAO's and/or the ROS's is sought in the firstplace.

According to another variant of the invention, the compounds of Examples1, 8 to 10 and 25 (sometimes described in the form of salts), or theirpharmaceutically acceptable salts, are preferred when a modulatingactivity on the sodium channels is sought in the first place. Morepreferentially, the compound of Example 1, or its pharmaceuticallyacceptable salts, will be preferred for preparing a medicament accordingto the invention when a modulating activity on the sodium channels issought in the first place.

A subject of the invention is also, as medicaments, the followingcompounds:

-   butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;-   N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;-   [4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;-   2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;-   N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;-   N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;-   2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;-   4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   (1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;-   4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;-   4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;    and pharmaceutically acceptable salts of the latter.

The invention also relates to the pharmaceutical compositionscontaining, as active ingredient, at least one of the followingcompounds

-   butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;-   N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;-   [4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;-   2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;-   N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;-   N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;-   2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;-   4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   (1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1R)-2-methyl-1-[4-(1H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;-   4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;-   4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;    or a pharmaceutically acceptable salt of one of these compounds.

The invention also relates to the following compounds as new industrialproducts:

-   butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;-   N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;-   2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;-   [4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;-   2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;-   N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;-   N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3    thiazol-2-yl]methyl}amine;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;-   N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;-   2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;-   4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;-   4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   (1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;-   N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;-   N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;-   ethyl    N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;-   4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;-   4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;    and salts of these compounds.

In certain cases, the compounds according to the present invention cancontain asymmetrical carbon atoms. As a result, the compounds accordingto the present invention have two possible enantiomeric forms, i.e. the“R” and “S” configurations. The present invention includes the twoenantiomeric forms and all combinations of these forms, including theracemic “RS” mixtures. For the sake of simplicity, when no specificconfiguration is indicated in the structural formulae or names, itshould be understood that the two enantiomeric forms and their mixturesare represented.

By salt is meant, in particular, in the present application additionsalts with organic or inorganic acids as well as the salts formed usingbases.

By pharmaceutically acceptable salt, is meant in particular the additionsalts with inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or withorganic acids such as acetate, maleate, fumarate, tartrate, succinate,citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate andstearate. Also included in the field of the present invention, when theycan be used, are the salts formed from bases such as sodium or potassiumhydroxide. For other examples of pharmaceutically acceptable salts,reference can be made to “Salt selection for basic drugs”, Int. J.Pharm. (1986), 33, 201-217.

The pharmaceutical compositions according to the present invention canbe in the form of solids, for example powders, granules, tablets,gelatin capsules, liposomes or suppositories. Appropriate solid supportscan be, for example, calcium phosphate, magnesium stearate, talc,sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or glycols, similarly theirmixtures, in varying proportions, in water.

The administration of a medicament according to the invention can bedone by topical, oral, parenteral route, by intramuscular injection,etc.

The administration dose envisaged for a medicament according to theinvention is comprised between 0.1 mg to 10 g according to the type ofactive compound used.

In accordance with the invention, the compounds of the invention can beprepared by the processes described below.

Preparation of the Compounds of the Invention

The compounds of the present invention can all be prepared according totechniques described in PCT publication WO 01/26656.

Unless defined otherwise, all the technical and scientific terms usedhere have the same meaning as that usually understood by an ordinaryspecialist in the field to which this invention belongs. Likewise, allpublications, patent applications, all patents and all other referencesmentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand must in no case be considered as limiting the scope of theinvention.

EXAMPLES Preparation 1:4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine

Stage 1: N-Boc-sarcosinamide:

15.0 g (0.120 mol) of sarcosinamide hydrochloride (N-Me-Gly-NH₂.HCl) isdissolved in dichloromethane containing 46.2 ml (0.265 mol) ofdiisopropylethylamine. The mixture is cooled down to 0° C. thenBoc-O-Boc (28.8 g; 0.132 mol) is added in fractions and the mixture isstirred overnight at ambient temperature. The reaction medium is thenpoured into ice-cooled water followed by extraction withdichloromethane. The organic phase is washed successively with a 10%aqueous solution of sodium bicarbonate and with water, then finally witha saturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from diisopropyl etherin order to produce a white solid with a yield of 72%. Melting point:103° C.

Stage 2: 2-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide:

16.0 g (0.085 mol) of the intermediate obtained in Stage 1 is dissolvedin dimethoxyethane (500 ml) and the solution obtained is cooled down to5° C. Sodium bicarbonate (28.5 g; 0.34 mol) then, in small portions,(P₂S₅)₂ (38.76 g; 0.17 mol) are added. The reaction medium is allowed toreturn to ambient temperature under stirring over 24 hours. Afterevaporation of the solvents under vacuum, a 10% aqueous solution ofsodium bicarbonate is added to the residue and the solution is extractedusing ethyl acetate. The organic phase is washed successively with a 10%aqueous solution of sodium bicarbonate and with water, then finally witha saturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from ether in order toproduce a white solid with a yield of 65%. Melting point: 150-151° C.

Stage 3:4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-2-thiazolemethanamine:

The intermediate obtained in Stage 2 (4.3 g; 2.11 mmol) andbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone (6.9 g; 2.11 mmol)are dissolved in benzene (75 ml) under an argon atmosphere, then themixture is stirred at ambient temperature for 12 hours.

The reaction medium is heated under reflux for 4 hours. Afterevaporation of the solvents, the residue is diluted with dichloromethaneand washed with a saturated solution of NaCl. The organic phase isseparated, dried over magnesium sulphate, filtered and concentratedunder vacuum. The expected product is obtained after chromatography on asilica column (eluent: 20% ethyl acetate in heptane) in the form of anoil which crystallizes very slowly in a refrigerator with a yield of28%. Melting point: 126.5-127.3° C.

Stage 4:4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine:

2.3 ml (29 mmol) of trifluoroacetic acid is added dropwise, at 0° C. toa solution of 2.5 g (5.8 mmol) of the intermediate obtained in Stage 3and 2 ml (1.6 mmol) of triethylsilane in 50 ml of dichloromethane. Afterstirring for one hour, the reaction mixture is concentrated under vacuumand the residue is diluted in 100 ml of ethyl acetate and 50 ml of asaturated solution of NaHCO₃. After stirring and decantation, theorganic phase is dried over magnesium sulphate, filtered andconcentrated under vacuum. The residue is taken up in heptane in orderto produce, after drying, a white solid with a yield of 73%. Meltingpoint: 136° C.

Stage 5:4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanaminehydrochloride:

2.0 g (0.602 mmol) of the intermediate obtained in Stage 4 is dissolvedin anhydrous ether. The solution is cooled down to 0° C. then 18 ml(1.81 mmol) of a 1N solution of HCl in ether is added dropwise. Themixture is allowed to return to ambient temperature under stirring.After filtering and drying under vacuum, a white solid is obtained witha yield of 92%. Melting point: 185.3-186.0° C.

Preparation 2:2,6-di(tert-butyl)-4-(2-{[methyl(2-propynyl)amino]methyl}-1,3-thiazol-4-yl)phenol

0.52 ml (3.7 mmol) of triethylamine and an excess of 0.56 g (7.5 mmol)of chloropropargyl are added dropwise at 0° C. to a solution of 0.5 g(1.5 mmol) of the compound of Preparation 1 in 15 ml of acetonitrile.After stirring overnight, the reaction mixture is concentrated undervacuum and the residue is diluted with dichloromethane and 50 ml of asaturated solution of NaCl. After stirring and decantation, the organicphase is separated and dried over magnesium sulphate, filtered andconcentrated under vacuum. The expected product is obtained afterchromatography on a silica column (eluent: 20% ethyl acetate inheptane). After evaporation, the pure fractions produce a white solidwith a yield of 20%. Melting point: 210-215° C.

MH+=371.20.

Preparation 3: benzyl{4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methylcarbamate

The compound is prepared according to an experimental protocol describedin the Patent Application WO 98/58934 (see preparation of intermediates26.1 and 26.2), using Z-Gly-NH₂ in place of the N-Boc sarcosinamide. Theexpected compound is obtained in the form of a pale yellow oil with ayield of 99%.

MH+=453.20.

Preparation 4:4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol

0.1 ml of a 40% solution of potassium hydroxide is added dropwise to asolution of 0.106 g (1.1 mmol) of the compound of Preparation 3 in 10 mlof methanol. After overnight stirring under reflux, the reaction mixtureis concentrated under vacuum and the residue is diluted withdichloromethane and washed with a 1N solution of HCl then with 50 ml ofa saturated solution of NaCl. The organic phase is separated and driedover magnesium sulphate, filtered and concentrated under vacuum. Theexpected product is obtained after chromatography on a silica column(eluent: 5% ethanol in dichloromethane) in the form of a brown foam witha yield of 76%.

MH+=319.29.

Preparation 5:2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-oxazoleethanol

[this is intermediate 1.C of the PCT Application WO 99/09829;alternatively, this compound can also be obtained according to theprocedure described in J. Med. Chem. (1996), 39, 237-245.]

Preparation 6:2,6-ditert-butyl-4-(4-{2-[methyl(2-propynyl)amino]ethyl}-1,3-oxazol-2-yl)phenol

The compound of Preparation 5 is converted to a brominated derivative,intermediate 3, according to the procedure indicated in Diagram 1(c) ofthe PCT Application WO 99/09829. Then the brominated derivative (0.5 g;1.31 mmol) is added to a solution of N-methylpropargylamine 0.34 ml(3.94 mmol) and potassium carbonate (1.11 g) in dimethylformamide (20ml). After overnight stirring at 80° C., the reaction mixture isconcentrated under vacuum and the residue is diluted withdichloromethane and 50 ml of a saturated solution of NaCl. Afterstirring and decantation, the organic phase is separated and dried overmagnesium sulphate, filtered and concentrated under vacuum. The expectedproduct is obtained after chromatography on a silica column (eluent: 50%ethyl acetate in heptane). After evaporation, the pure fractions producea yellow oil with a yield of 24%.

MH+=369.30.

Preparation 7:2,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenolhydrochloride

Stage 1: tert-butyl4-{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}-1-piperazinecarboxylate:

The experimental protocol used is identical to that described forPreparation 6, tert-butyl piperazinecarboxylate being used as startingproduct in place of the N-methylpropargylamine. A brown oil is obtainedwith a yield of 72%.

MH+=486.20.

Stage 2:2,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenolhydrochloride:

A stream of HCl gas is passed bubblewise into a solution at 0° C. of theintermediate obtained in Stage 1 (0.450 g; 9.27 mmol) in ethyl acetate(30 ml). The mixture is left to return to ambient temperature overnight.A stream of argon is passed through the reaction mass, then the powderobtained is filtered and washed with ethyl acetate then with ether inorder to produce a white solid with a yield of 70%. Melting point: >200°C.

Preparation 8:N-methyl[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]methanaminehydrochloride

Stage 1: 2-chloro-]-(10H-phenothiazin-2-yl)ethanone:

2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone (2.2 g; 5.55mmol; prepared according to a protocol described in J. Heterocyclic.Chem. (1978), 15, 175, followed by a Friedel-Crafts reaction) isdissolved hot in a mixture of acetic acid (20 ml) and 20% HCl (5.5 ml)and the mixture obtained is heated under reflux for 30 minutes. Thereaction mixture is allowed to cool down, the precipitate is filtered,the mixture rinsed with acetic acid (5 ml) and dried under vacuum, thesolid obtained is purified by crystallization from toluene in order toproduce a brown product with a yield of 82%. Melting point: 190-191° C.(value in the literature: 197-198° C.).

Stage 2: N-methyl[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]methanaminehydrochloride:

The intermediate obtained in Stage 1 (0.280 g; 1.0 mmol) and tert-butyl2-amino-2-thioxoethyl(methyl)carbamate (0.204 g; 1.0 mmol; described forexample in PCT Patent Application WO 98/58934) are dissolved in tolueneand the mixture is heated under reflux for 18 hours. After the tolueneis evaporated off and the reaction mixture cooled down to 0° C., thelatter is taken up in a 4N solution of HCl in dioxane (10 ml) and themixture stirred for one hour at 0° C. before allowing the temperature toreturn to ambient temperature. The solid formed is filtered and rinsedwith ether. The expected product is obtained after purification bycrystallization from hot acetic acid in order to obtain a greenishsolid. Melting point: >275° C.

Preparation 9: butyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

Stage 1: N-(butoxycarbonyl)-β-alanine:

A solution containing β-alanine (8.9 g; 0.1 mol) and 100 ml of a 1Nsolution of sodium hydroxide is cooled down to 10° C. n-butylchloroformate (13.66 g; 0.1 mol) and 50 ml of a 2N solution of sodiumhydroxide are added simultaneously. After stirring for 16 hours at 23°C., approximately 10 ml of a solution of concentrated hydrochloric acid(approximately 11 N) is added in order to adjust the pH to 4-5. The oilobtained is extracted with ethyl acetate (2×50 ml), washed with waterthen dried over magnesium sulphate. The product crystallizes fromisopentane in the form of a white powder (yield of 68%). Melting point:50.5° C.

Stage 2: butyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate:

A mixture of N-(butoxycarbonyl)-β-alanine (prepared in Stage 1; 5.67 g;0.03 mol) and caesium carbonate (4.89 g; 0.015 mol) in 100 ml of ethanolis stirred at 23° C. for 1 hour. The ethanol is eliminated byevaporation under reduced pressure in a rotary evaporator. The mixtureobtained is dissolved in 100 ml of dimethylformamide then4-phenyl-bromoacetophenone (8.26 g; 0.03 mol) is added. After stirringfor 16 hours, the solvent is evaporated off under reduced pressure. Themixture obtained is taken up in ethyl acetate then the caesium bromideis filtered. The ethyl acetate of the filtrate is evaporated and thereaction oil is taken up in a mixture of xylene (100 ml) and ammoniumacetate (46.2 g; 0.6 mol). The reaction medium is heated at reflux forapproximately one hour and 30 minutes then, after cooling down, amixture of ice-cooled water and ethyl acetate is poured into thereaction medium. After decantation, the organic phase is washed with asaturated solution of sodium bicarbonate, dried over magnesium sulphatethen evaporated under vacuum. The solid obtained is filtered then washedwith ether in order to produce a light beige-coloured powder (yield of50%). Melting point: 136.7° C.

MH+=364.3.

Preparation 10:2,5,7,8-tetramethyl-2-{2-1(methylamino)methyl]-1,3-thiazol-4-yl}-6-chromanolhydrochloride

Stage 1:6-hydroxy-N-methoxy-N,2,5,7,8-pentamethyl-2-chromanecarboxamide:

2.2 g (22.0 mmol) of O,N-dimethylhydroxylamine hydrochloride,triethylamine (6.2 ml), 3.0 g (22.0 mmol) of hydroxybenzotriazole and4.2 g (22.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride are added successively to a solution of 5.0 g (20.0 mmol)of (R,S) 6-hydroxy-2.5,7,8-tetramethyl-2-chromanecarboxylic acid(Trolox®) in 175 ml of DMF. After the reaction mixture is stirredovernight at 25° C., the mixture is diluted with ice-cooled water andstirring is maintained for another 30 minutes. The product is extractedusing 3 times 100 ml of ethyl acetate. The organic solution is washedsuccessively with a 10% aqueous solution of sodium bicarbonate, withwater, with a 10% aqueous solution of citric acid and finally with asaturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from ether in order toproduce a white-coloured solid with a yield of 63%. Melting point:139-140° C.

MH+=294.

Stage 2:1-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)ethanone:

A solution of methyllithium (1.6 M; 31.25 ml; 50.0 mmol) is addeddropwise at a temperature of −30° C. to a solution of 2.93 g (10.0 mmol)of the intermediate obtained in Stage 1 in 100 ml of THF and the mixtureis left under stirring for 1 hour at −10° C. The reaction medium ishydrolyzed with NH₄Cl in a saturated aqueous solution. The product isextracted using 3 times 150 ml of ethyl acetate. The organic phase isfinally washed with sodium chloride in a saturated aqueous solutionbefore being dried over magnesium sulphate, filtered and concentratedunder vacuum. The product obtained is purified by crystallization fromdiisopropyl ether in order to produce a white solid with a yield of80.7%. Melting point: 97-98° C.

MH+=248.

Stage 3:2-bromo-1-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)ethanone:

The intermediate obtained in Stage 2 (0.777 g; 3.13 mmol) is dissolvedin ethanol (25 ml) under a stream of argon. The solution is cooled downto 0° C. and bromine (0.18 ml; 4.20 mmol) is added in one go (see J. Am.Chem. Soc. (1999), 121, 24), then the mixture is stirred for 30 minutesallowing the temperature to rise to ambient temperature. The excessbromine is eliminated by bubbling through argon then the mixture is leftunder stirring for 2.5 hours. The ethanol is evaporated off and theproduct obtained is purified by crystallization from toluene. Afterfiltering and washing with isopentane, a brown solid is obtained with ayield of 36%. Melting point: decomposition from 125° C.

MH+=326.

Stage 4:2,5,7,8-tetramethyl-2-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-6-chromanolhydrochloride:

The experimental protocol used is analogous to that described for Stage2 of Preparation 8, the intermediate obtained in Stage 3 of the presentPreparation being used as the starting product instead of theintermediate obtained in Stage 1 of Preparation 8, and benzene replacingthe toluene as solvent. The product obtained is purified bycrystallization from a minimum amount of dichloromethane in order toproduce a white solid with a yield of 48%. Melting point: 153-155° C.

Preparation 11:3,5-ditert-butyl-4′-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-1,1′-biphenyl-4-olhydrochloride

Stage 1; 3′,5′ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-carboxylic acid:

5.0 g (1.41 mmol) of ethyl3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-carboxylate (Chem. Lett.(1998), 9, 931-932) is dissolved in ethanol (25 ml). The solution iscooled down to 0° C. then a 1N solution of soda is added dropwise. Afterstirring overnight at ambient temperature, the reaction medium is heatedunder reflux in order to complete the reaction. After evaporation of thesolvents and dilution of the residue with water, the mixture obtained isacidified with a 1N solution of HCl and extraction is carried out withdichloromethane. The organic phase is washed with sodium chloride in asaturated aqueous solution before being dried over magnesium sulphate,filtered and concentrated under vacuum. The product obtained is purifiedby crystallization from diisopropyl ether in order to produce ayellow-white solid with a yield of 47%. Melting point: >240° C.

Stage 2:3′,5′-ditert-butyl-4′-hydroxy-N-methoxy-N-methyl-1,1′-biphenyl-4-carboxamide:

The experimental protocol used is identical to that described for Stage1 of Preparation 10, with the acid obtained in Stage 1 of the presentPreparation replacing the Trolox® as starting product. A yellowish solidis obtained with a yield of 93%. Melting point: 175.6-177° C.

Stage 3: 1-(3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)ethanone:

The experimental protocol used is identical to that described for Stage2 of Preparation 10, the intermediate obtained in Stage 2 of the presentPreparation replacing the intermediate obtained in Stage 1 ofPreparation 10. A white solid is obtained with a yield of 74%. Meltingpoint: 144-144.7° C.

Stage 4:2-bromo-1-(3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)ethanone:

The experimental protocol used is identical to that described for Stage3 of Preparation 10, the intermediate obtained in Stage 3 of the presentPreparation replacing intermediate obtained in Stage 2 of Preparation10. A yellow-orange oil is obtained which is sufficiently pure to beused in the following stage (yield of 100%).

Stage 5: tert-butyl[4-(3′5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)-1,3-thiazol-2-yl]methyl(methyl)carbamate:

This compound is prepared according to the experimental protocoldescribed for Stage 3 of Preparation 1, using the intermediate obtainedin Stage 4 of the present Preparation instead ofbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expectedcompound is obtained in the form of a colourless oil with a yield of46%.

MH+=509.43.

Stage 6:3,5-ditert-butyl-4′-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-1,1′-biphenyl-4-olhydrochloride:

0.230 g (0.452 mmol) of the intermediate obtained in Stage 5 of thepresent Preparation is dissolved in ethyl acetate (20 ml). HCl gas isbubbled through the solution previously obtained cooled down to 0° C.The stirred mixture is then allowed to return to ambient temperature.The solid formed is filtered and washed with ethyl acetate then withether before being dried under vacuum. A white solid is obtained with ayield of 85%. Melting point: 220-221° C.

Preparation 12:2,6-dimethoxy-4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride

Stage 1: 4-acetyl-2,6-dimethoxyphenyl acetate:

3.0 g (15.3 mmol) of 3,5-dimethoxy-4-hydroxyacetophenone is dissolved indichloromethane (30 ml) and 2.53 g (18.3 mmol) of K₂CO₃ is added.Triethylamine (2.6 ml) is then added dropwise. The reaction medium iscooled down to 0° C. and acetyl chloride (1.31 ml; 18.3 mmol) is added.The mixture is stirred for 24 hours at ambient temperature then pouredinto ice-cooled water. After extraction with dichloromethane, theorganic phase is washed with sodium chloride in a saturated aqueoussolution before being dried over magnesium sulphate, filtered andconcentrated under vacuum. The product obtained is purified bycrystallization from ether in order to produce a white solid with ayield of 99%. Melting point: 145° C.

Stage 2: 4-(bromoacetyl)-2,6-dimethoxyphenyl acetate:

The intermediate obtained in Stage 1 (0.850 g; 3.57 mmol) is solubilizedin ethyl acetate then 1.35 g (6.07 mmol) of previously dried CuBr₂ isadded. The mixture is heated under reflux for 2.5 hours before beingleft to return to ambient temperature. Vegetable black is added and themixture is stirred for 10 minutes. After filtering and evaporating todryness, the solid obtained is taken up in diisopropyl ether. Afterfiltering, a grey solid is obtained with a yield of 75%. Melting point:124.2-126.3° C.

Stage 3:4-(2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-dimethoxyphenylacetate:

This compound is prepared according to the experimental protocoldescribed for Stage 3 of Preparation 1, using the intermediate obtainedin Stage 2 of the present Preparation instead ofbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expectedcompound is obtained in the form of a white solid with a yield of 55%.Melting point: 135.2-137.4° C.

Stage 4: tert-butyl[4-(4-hydroxy-3,5-dimethoxyphenyl)-1,3-thiazol-2-yl]methyl(methyl)carbamate:

0.530 g (1.25 mmol) of the intermediate obtained in Stage 3 is dissolvedin methanol (20 ml). The solution is cooled down using an ice bath thena 1N solution of NaOH is added dropwise. The mixture is left to returnto ambient temperature under stirring. After evaporation to dryness anddilution of the residue with water, the solution is neutralised usingcitric acid followed by extraction with dichloromethane. The organicphase is washed with sodium chloride in a saturated aqueous solutionbefore being dried over magnesium sulphate, filtered and concentratedunder vacuum. The product is obtained in the form of a yellow oil with ayield of 96%.

MH+=381.20.

Stage 5:2,6-dimethoxy-4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride:

The experimental protocol used is identical to that described for Stage6 of Preparation 11, the intermediate obtained in Stage 4 of the presentPreparation replacing the intermediate obtained ain Stage 5 ofPreparation 11. A light beige solid is obtained with a yield of 97%.Melting point: 229.8-232.0° C.

Preparation 13:2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol

[this is intermediate 6.d _(i)) of Patent Application EP 432 740]

Stage 1: [4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylpivalate

This compound is prepared according to a protocol identical to thatdescribed for Stage 3 of Preparation 1, using2-(tert-butylcarbonyloxy)thioacetamide instead of the2-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide andtoluene replacing the benzene. The expected compound is obtained in theform of a white solid with a yield of 100%. Melting point: 114.6-116.0°C.

Stage 2: 2, 6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol

The experimental protocol used is identical to that described for Stage4 of Preparation 12, the intermediate obtained in Stage 1 of the presentPreparation replacing the intermediate obtained in Stage 3 ofPreparation 12. A white solid is obtained with a yield of 88%. Meltingpoint: 126.4-127.4° C.

Preparation 14:2,6-ditert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenolhydrochloride

Stage 1: tert-butyl 2-cyanoethyl(methyl)carbamate:

0.1 mol of N-methyl-β-alaninenitrile is dissolved in dichloromethane(100 ml) containing 20.9 ml (0.12 mol) of diisopropylethylamine. Themixture is then cooled down to 0° C. then Boc-O-Boc (26.2 g; 0.12 mol)is added by fractions, then the mixture is stirred overnight at ambienttemperature. The reaction medium is then poured into ice-cold water andextracted with dichloromethane. The organic phase is washed successivelywith a 10% aqueous solution of sodium bicarbonate and with water, thenfinally with a saturated solution of sodium chloride. The organic phaseis then dried over magnesium sulphate, filtered and concentrated undervacuum. The reddish brown oil obtained is used as it is in the followingstage.

Stage 2: tert-butyl 3-amino-3-thioxopropyl(methyl)carbamate:

43.4 mmol of the intermediate obtained in Stage 1 is dissolved inethanol (40 ml) containing triethylamine (6.1 ml). H₂S is then bubbledthrough the mixture for 3 hours before evaporating the solvents todryness. The expected product is obtained after chromatography on asilica column (eluent: 50% ethyl acetate in heptane) in the form of alight orange oil. Crystallization of this oil from diisopropyl ethergives a white solid with a yield of 15%. Melting point: 104° C.

Stage 3:4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-2-thiazoleethanamine:

The intermediate obtained in Stage 2 (2.11 mmol) andbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone (6.9 g; 2.11 mmol)are dissolved in toluene (75 ml) under an argon atmosphere then themixture is stirred at ambient temperature for 12 hours. The reactionmedium is heated at reflux for 4 hours. After evaporation of thesolvents, the residue is diluted with dichloromethane and washed with asaturated solution of NaCl. The organic phase is separated, dried overmagnesium sulphate, filtered and concentrated under vacuum. The expectedproduct is crystallized in the form of a white solid. Melting point:204° C.

Stage 4:2,6-ditert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenolhydrochloride:

1.95 mmol of the intermediate obtained in Stage 3 is dissolved in ethylacetate (20 ml). The solution is cooled down to 0° C. then HCl gas isbubbled through for 10 minutes. The mixture is left to return to ambienttemperature while stirring is maintained. After filtration and dryingunder vacuum, the expected product is recovered in the form of whitecrystals which are washed with ether. Quantitative yield. Melting point:206-208° C.

Preparation 15:2,6-ditert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol

Stage 1: [4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylpivalate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 3 of Preparation 14, using2-(tert-butylcarbonyloxy)thioacetamide instead of the intermediateobtained in Stage 2 of Preparation 14 and with toluene replacing thebenzene. The expected compound is obtained in the form of a white solidwith a yield of 100%. Melting point: 114.6-116.0° C.

Stage 2: 2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol:

The intermediate obtained in Stage 1 (1.25 mmol) is dissolved inmethanol (20 ml). The solution is cooled down using an ice bath then a1N solution of NaOH is added dropwise. The mixture is left to return toambient temperature while stirring. After evaporation to dryness anddilution of the residue with water, the solution is neutralized usingcitric acid and extraction is carried out with dichloromethane. Theorganic phase is washed with sodium chloride in a saturated aqueoussolution before being dried over magnesium sulphate, filtered andconcentrated under vacuum. A white solid is obtained with a yield of88%. Melting point: 126.4-127.4° C.

Stage 3: 2,6-ditert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol:

The intermediate obtained in Stage 2 (1 equivalent) is methylated byreaction with 1.1 equivalent of iodomethyl in the presence of 2equivalents of triethylamine, the reaction being carried out intetrahydrofuran. A dark cream powder is obtained. Melting point:115.8-117° C.

Preparation 16:2,6-ditert-butyl-4-[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]phenol

Stage 1: 4-[2-(bromomethyl)-1,3-thiazol-4-yl]-2,6-ditert-butylphenol:

1.5 g (4.70 mmol) of the intermediate obtained in Stage 2 of Preparation15, (2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol, aredissolved in dichloromethane (30 ml). After adding CBr₄ (2.02 g; 6.10mmol), the reaction medium is cooled down to 0° C. PPh₃ (1.48 g; 5.63mmol) is added by fractions then the mixture is allowed to return toambient temperature. The reaction medium is then poured into ice-coldwater before being extracted with dichloromethane. The organic phase iswashed with salt water before being dried over magnesium sulphate,filtered and concentrated under vacuum. The expected product is obtainedafter chromatography on a silica column (eluent: 30% of ethyl acetate inheptane), in order to produce a brown oil with a yield of 92%. Thisproduct is sufficiently pure to be able to be used directly in thefollowing stage.

MH+=382.20.

Stage 2:2,6-ditert-butyl-4-[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]phenol:

1.57 mmol of morpholine and 0.4 ml (2.62 mmol) of triethylamine aredissolved in dimethylformamide (15 ml). 0.400 g (1.05 mmol) of theintermediate obtained in Stage 1 dissolved in dimethylformamide (5 ml)is added then the mixture is stirred at ambient temperature for 18hours. The reaction medium is then poured into ice-cold water andextraction is carried out with ethyl acetate. The organic phase iswashed with salt water before being dried over magnesium sulphate,filtered and concentrated under vacuum. The expected product is obtainedafter chromatography on a silica column (eluent: 50% ethyl acetate inheptane), in order to produce an orange oil with a yield of 92%. Lightcream crystals are obtained. Melting point: 136.7-137.2° C.

Example 1 butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate

1.1) butyl 2-[4-(4-nitrophenyl)-1H-imidazol-2-yl]ethylcarbamate:

This compound is prepared according to a protocol identical to thatdescribed for Preparation 9, 4-nitrophenacyl bromide replacing4-phenyl-bromoacetophenone in Stage 2. The expected product is obtainedin the form of brown powder with a yield of 1%.

MH+=333.20.

1.2) butyl 2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate:

Intermediate 1.1 (0.28 g, 0.84 mmol) is dissolved in 20 ml of ethanol.0.02 g of palladium on carbon (10%) is added and the mixture is placedunder a hydrogen atmosphere (pressure of 2 bars). The catalyst isrecovered by filtration then the solvent is evaporated off under reducedpressure. The expected product is purified by chromatography on a silicacolumn (eluent=8% methanol and 0.5% ammonia in dichloromethane) in orderto produce a brown powder with a yield of 24%. Melting point: 120° C.

Example 2N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine

2.1) N-[(benzyloxy)carbonyl]-N-methylvaline:

10.0 g (0.0762 mol) of N-(Me)-(DL)-Valine-OH is dissolved in adioxane/water mixture (90/10; 100 ml) and pH is adjusted to 11 using a1N sodium hydroxide aqueous solution. Benzyloxysuccinimide (20.9 g;0.0839 mol) in dioxane (40 ml) is added dropwise and the mixture isstirred overnight at room temperature. The reaction medium is thenpoured into ice-cooled water and acidified using a 10% aqueous citricacid solution before being extracted with ethyl acetate. The organicphase is washed with a saturated solution of sodium chloride. Theorganic phase is then dried over magnesium sulphate, filtered andconcentrated under vacuum. The residue is purified on a silica column(eluent: 5% ethanol in dichloromethane) producing the title compound inthe form of a pale yellow oil with a yield of 64%.

MH+=266.10.

2.2) N-(Methyl)(CBZ)-(DL)-Valine-NH₂:

Hydroxybenzotriazole (100 g; 0.653 mol) is suspended in methanol (500ml), aqueous ammonium hydroxide 28% (60 ml) is added dropwise at ambienttemperature and the suspension slowly goes into solution beforeprecipitation, stirring being continued for approximately 5 hours. Themethanol is evaporated off and the white solid triturated withisopropylether. The solid is filtered and washed with isopropyl ether inorder to produce the HOBT.NH₃ complex in the form of a white powder witha 76% yield.

Intermediate 2.1 (12.9 g; 0.0486 mol), HOBT.NH₃ (as prepared previously;9.1 g; 0.0584 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium-hexafluorophosphate(BOP) (21.5 g; 0.0486 mol) are dissolved in DMF (120 ml) under an argonatmosphere. The mixture is cooled down to 0° C. anddi-isopropylethylamine (18.7 ml) is added dropwise. The reaction mediumis left to return to ambient temperature with stirring overnight. Thereaction medium is then poured into ice-cooled water and extraction withethyl acetate carried out. The organic phase is washed with a 10%aqueous sodium bicarbonate solution followed by a saturated solution ofsodium chloride. The organic phase is then dried over magnesiumsulphate, filtered and concentrated under vacuum. The solid residue istriturated with ether, the solid is filtered to produce a whitehygroscopic solid with a yield of 83%, which is used directly in thenext stage.

MH+=265.20

2.3) Benzyl 1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 1.2 of Example 1, intermediate 2.2 replacingintermediate 1.1. The expected product is obtained in the form of awhite solid with a yield of 36%. Melting point: 130° C.

2.4) Benzylmethyl{2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}carbamate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 1.3 of Example 1, intermediate 2.3 replacingintermediate 1.2,2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone replacingbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone and toluene replacingbenzene. The expected product is obtained in the form of a yellow-orangefoam with a yield of 49%.

MH+=502.10.

2.5)N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine:

Intermediate 2.4 (1.2 g; 0.00238 mol) is dissolved in glacial acetic (12ml). Concentrated HCl (4 ml) is added dropwise and the mixture is thenheated at 100° C. for 2 hours before being evaporated to dryness. Theresidue is taken up in dichloromethane and washed with a 10% aqueoussodium bicarbonate solution then with saturated solutions of sodiumchloride until the aqueous phase is neutral (pH paper). The organicphase is then dried over magnesium sulphate, filtered and concentratedunder vacuum. The residue is purified on an reversed-phase silica columnRP 18 (eluent: 40% aqueous (0.1N) TFA in acetonitrile). The combinedfractions are evaporated to dryness, a 10% aqueous sodium bicarbonatesolution is added to the residue and the mixture extracted withdichloromethane then with a saturated solution of sodium chloride. Theorganic phase is then dried over magnesium sulphate, filtered andconcentrated under vacuum. The solid is triturated with isopentane toproduce the title compound in the form of a yellow-orange solid with ayield of 14%. Melting point: 143.2-144.0° C.

Example 3N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine

The experimental protocol used is identical to that described forExample 2, 2-chloro-1-[10-(chloroacetyl)-10H-phenoxazine-2-yl)ethanonereplacing 2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanoneto finally produce the title compound in the form of a chestnut foam.MH+=352.2.

Example 4N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine

The experimental protocol used is identical to that described forExample 2, thioamide benzyl1-(aminocarbonothioyl)-3-methylbutyl(methyl)carbamate (prepared in thesame way as intermediate 2.3) replacing benzyl1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate and2-chloro-1-[10-(chloroacetyl)-10H-phenoxazine-2-yl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone in Stage2.4 in order to finally produce the title compound in the form of abeige solid. Melting point: 143.1-147.0° C.

Example 5N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine

The experimental protocol used is identical to that described forExample 2, thioamidebenzyl-1-(aminocarbonothioyl)-3-methylbutyl(methyl)carbamate (preparedin the same way as the intermediate 2.3) replacing benzyl1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate in Stage 2.4, inorder to finally produce the title compound in the form of yellowcrystals. Melting point: 145.7-148.1° C.

Example 6 hydrochloride salt of2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol

The experimental protocol used is identical to that described forExample 2, thioamidebenzyl-1-(aminocarbonothioyl)-3-methylbutyl(methyl)carbamate (preparedin the same way as the intermediate 2.3) replacing benzyl1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate and2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone in Stage2.4 during which removal of the CBZ protective group occurred in situ.The resulting free base compound is purified by normal phasechromatography on a silica-gel column (eluent: 30% ethyl acetate inheptane). After treatment of the free base using 1N HCl in ether, thetitle compound is obtained in the form of a creamy-white solid with anoverall yield of 13%. Melting point: 148.1-149.0° C.

Example 7 hydrochloride salt of[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine

The experimental protocol used is identical to that described forExample 2, thioamide benzyl 2-amino-2-thioxoethylcarbamate (prepared inthe same way as intermediate 2.3) replacing intermediate 2.3 and2-bromo-1-(3,5-ditert-butyl-phenyl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone in Stage2.4. The deprotection of the CBZ protective group is carried out in thesame way as in Stage 2.5. The formed free base compound is purified bynormal phase chromatography on a silica-gel column (eluent: 10% ethylacetate in heptane). After treatment of the free base using 1N HCl inether, the title compound is obtained in the form of a creamy-whitesolid. Melting point: 207.0-209.6° C.

Example 8 hydrochloride salt of2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol

The experimental protocol used is identical to that described forExample 2, thioamide benzyl(1S)-2-amino-1-methyl-2-thioxoethyl(methyl)carbamate replacingintermediate 2.3 and2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone. Thedeprotection of the (CBZ) protective group is carried out in the sameway as in stage 2.5. The formed free base compound is purified by normalphase chromatography on a silica-gel column (eluent: 3% ethanol indichloromethane). After treatment of the free base using 1N HCl inether, the title compound is obtained in the form of a white crystallinesolid. Melting point: 240.6-242.0° C.

Example 9 hydrochloride salt of2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol

The experimental protocol used is identical to that described forExample 8, thioamide benzyl(1R)-2-amino-1-methyl-2-thioxoethyl(methyl)carbamate replacing thioamidebenzyl (1S)-2-amino-1-methyl-2-thioxoethyl(methyl)carbamate, in order tofinally produce, after formation of the salt, the title compound as awhite crystalline solid. Melting point: 242.8-243.6° C.

Example 10 hydrochloride salt ofN-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine

The experimental protocol used is identical to that described forPreparation 1, 2-bromo-1-(3,5-ditert-butyl-phenyl)ethanone replacing2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone in Stage 3.Elimination of the N-(Boc) protective group and formation of the saltare carried out in one stage using HCl gas according to a protocolsimilar to that described for Preparation 7, Stage 2 in order to producethe title compound in the form of a creamy-white solid. Melting point:212.2-213.9° C.

Example 11 hydrochloride salt ofN-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine

11.1) 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone:

The experimental protocol used is identical to that described forPreparation 12, Stage 2, commercially available3,4,5-trimethoxy-acetophenone replacing the intermediate obtained inStage 1 of Preparation 12. Intermediate 11.1 is obtained afterchromatography on a silica column (eluent: 50% ethyl acetate in heptane)in the form of a yellow solid with a yield of 66%.

MH+=289.01

11.2) Hydrochloride salt ofN-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine:

This compound is obtained using the same protocol as that described forPreparation 1, intermediate 11.1 replacing2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone in Stage 4.Elimination of the Boc protective group and formation of the salt werecarried out in one stage using HCl gas according to a protocol similarto that described for Preparation 7, Stage 2 in order to produce thetitle compound in the form of a yellow crystalline solid. Melting point:199.4-200.6° C.

Example 12 hydrochloride salt of ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate

The experimental protocol used is identical to that described forPreparation 2, ethyl bromoacetate replacing chloropropargyl and thecompound of Preparation 4 replacing the compound of Preparation 1. Aftertreatment of the free base using 1N HCl in ether, the title compound isobtained in the form of a white crystalline solid with an overall yieldof 69%. Melting point: 164.0-167.0° C.

Example 13 hydrochloride salt ofN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine

13.1) EthylN-(tert-butoxycarbonyl)-N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate

The experimental protocol used is identical to that described forPreparation 14, Stage 1, the compound of Example 12 replacingN-methyl-β-alaninenitrile, triethylamine being used instead ofdiisopropylethylamine and a catalytic amount of dimethylaminopyridine(DMAP) being added to carry out the reaction. The title compound isobtained in the form of a green oil which is used directly in the nextstage.

MH+=505.30.

13.2)N-(tert-butoxycarbonyl)-N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine

1.0 g (1.98 mmol) of intermediate 13.1 is dissolved in THF (20 ml). Asolution of lithium hydroxide (1N in water) is added dropwise and thereaction medium is left under stirring at ambient temperature for 6hours. The reaction medium is then poured into water followed byextraction with diethyl ether. The aqueous phase is acidified withaqueous HCl (1N) and extracted with diethyl ether. The organic phase iswashed with a saturated solution of sodium chloride, then dried overmagnesium sulphate, filtered and concentrated under vacuum before beingused directly in the next stage.

MH+=477.20.

13.3) Hydrochloride salt ofN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-ylmethyl}glycine

The experimental protocol used is identical to that described forPreparation 7, Stage 2, intermediate 13.2 replacing the intermediateobtained in Stage 1 of Preparation 7. The title compound is obtained inthe form of a white crystalline solid with a yield of 27%.

MH+=377.2.

Example 14 hydrochloride salt of2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol

The experimental protocol used is identical to that described forPreparation 16, Stage 2,4-methoxy-piperidine replacing morpholine. Thetitle compound is obtained in the form of a white crystalline solid.Melting point: 198.0-201.0° C.

Example 15 hydrochloride salt ofN-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine

This compound is prepared in an analogous way to the compound of Example2, however using optically pure starting material, namelyN-(Me)-(L)-Valine-OH instead of N-(Me)-(DL)-Valine-OH). Melting point:270.0-270.8° C.

Example 16 hydrochloride salt ofN,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine

16.1)Benzylmethyl{2-methyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}carbamate

Intermediate 2.4 was methylated according to the following procedure:0.200 g (0.410 mmol) of intermediate 2.4 is dissolved in dioxane (10ml). Sodium hydride (0.024 g; 0.598 mmol) is added in small portions andthe mixture is left under stirring for 30 minutes. Iodomethane (0.04 ml)is added dropwise and the reaction medium is heated at 45 C for 18hours. Ethanol (10 ml) is added dropwise and the reaction medium is thenpoured into water before being extracted with ethyl acetate. The organicphase is washed with a saturated solution of sodium chloride, then driedover magnesium sulphate, filtered and concentrated under vacuum.Intermediate 16.1 is obtained after chromatography on a silica column(eluent: 15% ethyl acetate in heptane) as a yellow gummy solid with ayield of 42%.

MH+=516.10.

16.2) Hydrochloride salt ofN,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine

Intermediate 16.1 is dissolved in a glacial acetic acid/water/methanol(30 ml) mixture. A catalytic amount of Pd/C is added and the reactionmedium is hydrogenated at ambient temperature under a pressure of 5 barsfor 12 hours. The exhausted catalyst is filtered off and the filtratewas evaporated to dryness and azeotropic distillation with toluene iscarried out several times. The hydrochloride salt, a grey solid, isobtained using a 1N HCl solution in ether with an overall yield of 45%.

MH+=382.10.

Example 17 hydrochloride salt ofN-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine

This compound is prepared in an analogous way to the compound of Example3, however using optically pure starting material, namelyN-(Me)-(CBZ)-(L)-Valine-OH instead of N-(Me)-(DL)-Valine-OH. A greypowder is obtained.

MH+=352.2.

Example 18 hydrochloride salt of4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol

The experimental protocol used is identical to that described for thecompound of Example 2, thioamide benzyl(1R)-2-amino-1-methyl-2-thioxoethylcarbamate (prepared in a similar wayto the intermediate 2.3) replacing thioamide benzyl1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate and2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone in thefourth stage. The title hydrochloride salt is then obtained as a whitesolid using 1N HCl in ether. Melting point: 211.8-215.2° C.

Example 19 hydrochloride salt of4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol

The experimental protocol used is identical to that described forExample 2, thioamide benzyl (1S)-2-amino-1-methyl-2-thioxoethylcarbamate(prepared in a similar way to the intermediate 2.3) replacing thioamidebenzyl 1-(aminocarbonothioyl)-2-methylpropyl(methyl)carbamate and2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone replacing2-chloro-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone in thefourth stage. The title hydrochloride salt is then obtained as a whitesolid using 1N HCl in ether. Melting point: 191.0-195.0° C.

Example 20 hydrochloride salt of4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol

20.1) tert-butyl [1-(aminocarbonyl)cyclopropyl]carbamate:

The experimental protocol used is identical to that described for Stage2 of Example 2, 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylicacid replacing intermediate 2.1. The title compound is obtained in theform of a colourless oil used directly in the next stage.

20.2) Tert-butyl [1-(aminocarbonothioyl)cyclopropyl]carbamate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 2 of Preparation 1, intermediate 20.1 replacing theintermediate obtained in Stage 1 of Preparation 1. The expected productis obtained in the form of a yellow oil used directly in the next stage.

20.3) Hydrochloride salt of4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol:

This compound is prepared according to a protocol identical to thatdescribed for Stage 3 of Preparation 1, intermediate 20.2 replacing theintermediate obtained in Stage 2 of Preparation 1 and toluene replacingbenzene. Deprotection of the N-(Boc) protective group occurs in-situ.The hydrochloride salt is then obtained in the form of a white-creamysolid using 1N HCl in ether. Melting point: 200.6-202.2° C.

Example 21 hydrochloride salt of4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol

The experimental protocol used is identical to that described forPreparation 1, 2-chloro-3′,4′-dihydroxyacetophenone replacing2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The title compoundis obtained in the form of a white-creamy solid.

MH+=237.0.

Example 22 hydrochloride salt ofN-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine

This compound is prepared in an analogous way to Example 2, howeverusing optically pure starting material, i.e. N-(Me)-(CBZ)-(D)-Valine-OHinstead of N-(Me)-(DL)-Valine-OH. The title compound is obtained in theform of a light green powder. Melting point: 265.6-268.9° C.

Example 23 hydrochloride salt of(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine

23.1) tert-butyl(1R)-1-[4-(10-acetyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]-2-methylpropylcarbamate

The experimental protocol used is identical to that described forPreparation 1, 1-(10-acetyl-10H-phenothiazin-2-yl)-2-bromoethanone(Arzneimittel Forschung (1962), 12, 48-52) replacing2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone and thioamidetert-butyl (1R)-1-(aminocarbonothioyl)-2-methylpropylcarbamate (preparedin a similar way to the intermediate obtained in Stage 2 ofPreparation 1) replacing the intermediate obtained in Stage 2 ofPreparation 1. Elimination of the N-(Boc) protective group and formationof the salt are carried out in one stage using HCl gas according to aprocedure similar to that described for Stage 2 of Preparation 7. Thetitle compound is obtained in the form of a grey solid.

MH+=396.1.

23.2) Hydrochloride salt of(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine:

Intermediate 23.1 is dissolved in 2N HCl and refluxed for 18 hours. Thesolution is extracted with ethyl acetate and the aqueous phase is madebasic using an aqueous solution (10%) of sodium bicarbonate andextracted with ethyl acetate. The organic phase is washed with a 10%aqueous sodium bicarbonate solution then with a saturated solution ofsodium chloride. The organic phase is dried over magnesium sulphate,filtered and concentrated under vacuum. The residue is purified on asilica column (eluent: 5% ethanol in dichloromethane), producing thefree base as a pale brown oil. The hydrochloride salt is obtained in theform of a green powder using 1N HCl in ether.

MH+=354.2.

Example 24 hydrochloride salt ofN-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine

This compound is prepared in an analogous way to Stages 2.2 to 2.5 ofExample 2, however using optically pure starting material, namelyN-(Me)-(CBZ)-(D)-Valine-OH instead of intermediate 2.1. The titlehydrochloride salt is obtained as in the form of a yellow powder.

MH+=352.2.

Example 25 hydrochloride salt ofN²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide

The experimental protocol used is identical to that described forPreparation 2, 2-bromoacetamide replacing chloropropargyl and thecompound of Preparation 4 replacing the compound of Preparation 1. Thehydrochloride salt is then obtained in the form of a white powder using1N HCl in ether.

MH+=376.2.

Example 26 hydrochloride salt of ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate

The experimental protocol used is identical to that described forPreparation 2, with however an excess of ethyl bromoacetate replacingchloropropargyl and the compound of Preparation 4 replacing the compoundof Preparation 1. The hydrochloride salt is then obtained in the form ofa white foam using 1N HCl in ether.

MH+=491.2.

Example 27 hydrochloride salt of4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole

The experimental protocol used is identical to that described for Stage16.1 of Example 16, the intermediate obtained in Stage 1 of Preparation13 replacing intermediate 2.4 and THF replacing dioxane. The titlecompound is obtained in the form of a white solid with a yield of 38%.Melting point: 94.0-94.8° C.

Example 28 hydrochloride salt of4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol

28.1) tert-butyl [1-(aminocarbonyl)cyclopentyl]carbamate:

The experimental protocol used is identical to that described for Stage2 of Example 2, 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylicacid replacing intermediate 2.1. The title compound is obtained as awhite flaky solid which is used directly in the next stage.

28.2) tert-butyl [1-(aminocarbonothioyl)cyclopentyl]carbamate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 2 of Preparation 1, intermediate 28.1 replacing theintermediate obtained in Stage 1 of Preparation 1. The expected productis obtained in the form of a white flaky solid which is used directly inthe next stage.

MH+=245.2.

28.3) tert-butyl{1-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]cyclopentyl}carbamate:

This compound is prepared according to a protocol identical to thatdescribed for Stage 3 of Preparation 1, intermediate 28.2 replacing theintermediate obtained in Stage 2 of Preparation 1 and toluene replacingbenzene. The expected product is obtained in the form of a colourlessoil.

MH+=473.4.

28.4) Hydrochloride salt of4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol:

Elimination of the N-(Boc) protective group from intermediate 28.3 andformation of the salt are carried out in one stage using HCl gasaccording to a protocol similar to that described for Stage 2 ofPreparation 7. The title compound is obtained in the form of a whitecrystalline solid. Melting point: 288.8-290.7° C.

Pharmacological Study of the Products of the Invention

Study of the Effects on the Bond of a Specific Ligand of MAO-B, [³H]Ro19-6327

The inhibitory activity of the products of the invention is determinedby measurement of their effects on the bond of a specific ligand ofMAO-B, [³H]Ro 19-6327.

a) Mitochondrial Preparation of the Cortex of Rats

The mitochondrial preparation of the cortex of rats is carried outaccording to the method described in Cesura A M, Galva M D, Imhof R andDa Prada M, J. Neurochem. 48 (1987), 170-176. The rats are decapitatedand their cortex is removed, homogenized in 9 volumes of a 0.32 Msucrose buffer, buffered to pH 7.4 with 5 mM of HEPES, then centrifugedat 800 g for 20 minutes. The supernatants are recovered and the pelletsare washed twice with the 0.32 M sucrose buffer as previously. Thecollected supernatants are centrifuged at 10000 g for 20 minutes. Thepellets obtained are suspended in a Tris buffer (50 mM Tris, 130 mMNaCl, 5 mM KCl, 0.5 mM EGTA, 1 mM MgCl₂, pH 7.4) and centrifuged at10000 g for 20 minutes. This stage is repeated twice, and the finalpellet, corresponding to the mitochondrial fraction, is stored at −80°C. in the Tris buffer. The protein content of the preparation isdetermined by the Lowry method.

b) Bond of [³H]Ro 19-6327

100 μl of the mitochondrial preparation (2 mg protein/ml) are incubatedfor 1 hour at 37° C. in an Eppendorf tube, in the presence of 100 μl of[³H]Ro 19-6327 (33 nM, final concentration) and 100 μl of Tris buffercontaining or not containing the inhibitors. The reaction is stopped bythe addition of 1 ml of cold Tris buffer into each tube, then thesamples are centrifuged for 2 minutes at 12000 g. The supernatants areremoved by suction and the pellets washed with 1 ml of Tris buffer. Thepellets are then solubilized in 200 μl of sodium dodecyl sulphate (20%weight/volume) for 2 hours at 70° C. The radioactivity is determined bycounting the samples using liquid scintillation.

c) Results

The compound of Example 9 described above shows an IC₅₀ lower than 10μM. Moreover, the compounds of Examples 8, 18 and 19 described aboveshow an IC₅₀ lower than 20 μM.

Study of the Effects on Lipidic Peroxidation of the Cerebral Cortex ofthe Rat

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipidic peroxidation,determined by the concentration of malondialdehyde (MDA). The MDAproduced by peroxidation of unsaturated fatty acids is a good indicationof lipidic peroxidation (H Esterbauer and K H Cheeseman, Meth. Enzymol.(1990) 186: 407-421). Male Sprague Dawley rats weighing 200 to 250 g(Charles River) were sacrificed by decapitation. The cerebral cortex isremoved, then homogenized using a Thomas potter in a 20 mM Tris-HClbuffer, pH=7.4. The homogenate is centrifuged twice at 50000 g for 10minutes at 4° C. The pellet is stored at −80° C. On the day of theexperiment, the pellet is resuspended at a concentration of 1 g/15 mland centrifuged at 515 g for 10 minutes at 4° C. The supernatant is usedimmediately to determine the lipidic peroxidation. The homogenate ofrat's cerebral cortex (500 μl) is incubated at 37° C. for 15 minutes inthe presence of the compounds to be tested or of the solvent (10 μl).The lipidic peroxidation reaction is initiated by adding 50 μl of FeCl₂at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After incubation for 30minutes at 37° C., the reaction is stopped by adding 50 μl of a solutionof hydroxylated di-tert-butyl toluene (BHT, 0.2%). The MDA is quantifiedusing a colorimetric test, by reacting a chromogenic reagent (R),N-methyl-2-phenylindol (650 μl) with 200 μl of the homogenate for 1 hourat 45° C. The condensation of an MDA molecule with two molecules ofreagent R produces a stable chromophore the maximum absorbencewavelength of which is equal to 586 nm (Caldwell et al., European J.Pharmacol. (1995), 285, 203-206). The compounds of Examples 2 to 6, 8, 9and 12 to 26 described above show an IC₅₀ lower than 10 μM.

Bond Test on the Cerebral Sodium Channels of the Cortex of the Rat

The test consists in measuring the interaction of the compoundsvis-à-vis the bond of tritiated batrachotoxin on the voltage-dependentsodium channels according to the protocol described by Brown (J.Neurosci. (1986), 6, 2064-2070).

Preparation of Homogenates of Cerebral Cortices of the Rat

The cerebral cortices of Sprague-Dawley rats weighing 230-250 g (CharlesRiver, France) are removed, weighed and homogenized using a Potterhomogenizer provided with a teflon piston (10 strokes) in 10 volumes ofisolation buffer the composition of which is as follows (sucrose 0.32 M;K₂HPO₄ 5 mM; pH 7.4). The homogenate is subjected to a firstcentrifugation at 1000 g for 10 minutes. The supernatant is removed andcentrifuged at 20000 g for 15 minutes. The pellet is taken up in theisolation buffer and centrifuged at 20000 g for 15 minutes. The pelletobtained is resuspended in incubation buffer (HEPES 50 mM; KCl 5.4 mM;MgSO₄ 0.8 mM; glucose 5.5 mM; choline chloride 130 mM pH 7.4) thenaliquoted and stored at −80° C. until the day of assay. The finalprotein concentration is comprised between 4 and 8 mg/ml. The assay ofproteins is carried out using a kit marketed by BioRad (France).

Measurement of the Bond of Tritiated Batrachotoxin

The bond reaction is carried out by incubating for 1 hour 30 minutes at25° C. 100 μl of homogenate of rat cortex containing 75 μg of proteinswith 100μl of [³H] batrachotoxin-A 20-alpha benzoate (37.5 Ci/mmol, NEN)at 5 nM (final concentration), 200 μl of tetrodotoxin at 1 μM (finalconcentration) and scorpion venom at 40 μg/ml (final concentration) and100 μl of incubation buffer alone or in the presence of the products tobe tested at different concentrations. The non-specific bond isdetermined in the presence of 300 μM of veratridine and the value ofthis non-specific bond is subtracted from all the other values. Thesamples are then filtered using a Brandel (Gaithersburg, Md., USA) usingUnifilter GF/C plates pre-incubated with 0.1% of polyethylene imine (20μl/well) and rinsed twice with 2 ml of filtration buffer (HEPES 5 mM;CaCl₂ 1.8 mM; MgSO₄ 0.8 mM; choline chloride 130 mM; BSA 0.01%; pH 7.4).After having added 20 μl of Microscint 0®, the radioactivity is countedusing a liquid scintillation counter (Topcount, Packard). Themeasurement is carried out in duplicate. The results are expressed as a% of the specific bond of tritiated batrachotoxin relative to thecontrol.

Results

The compounds of Examples 1, 8 to 10 and 25 described above all show anIC₅₀ lower than or equal to 1 μM.

1. A compound: butyl2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine;ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;4-(2-[(methylamino)methyl]-1,3-thiazol-4-yl)benzene-1,2-diol;N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;(1R)-2-methyl-1-[4-(10H-phenothiazin-2-y1)-1,3-thiazol-2-yl]propan-1-amine;N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol; orsalts or combinations thereof.
 2. A compound according to claim 1,wherein the compound is butyl2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate or a salt thereof.3. A compound or salt according to claim 1, wherein the compound is4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol or asalt thereof.
 4. A medicament, comprising a compound: butyl2-[4-(4-aminophenyl)-1H-imidazol-2-yl]ethylcarbamate;N,2-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N,2-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N,3-dimethyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;N,3-dimethyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]butan-1-amine;2,6-di-tert-butyl-4-{2-[3-methyl-1-(methylamino)butyl]-1,3-thiazol-4-yl}phenol;[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methylamine;2,6-di-tert-butyl-4-{2-[(1S)-1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;2,6-di-tert-butyl-4-{2-[(1R)-1-(methylamriino)ethyl]-1,3-thiazol-4-y1}phenol;N-{[4-(3,5-di-tert-butylphenyl)-1,3-thiazol-2-yl]methyl}-N-methylamine;N-methyl-N-{[4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-yl]methyl}amine;ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinate;N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycine;2,6-di-tert-butyl-4-{2-[(4-methoxypiperidin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;N-methyl-N-{(1S)-2-methyl-1-(4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;N,2-dimethyl-1-[4-(10-methyl-10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N-methyl-N-{(1S)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;4-[2-(1-aminocyclopropyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}benzene-1,2-diol;N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;(1R)-2-methyl-1-(4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]propan-1-amine;N-methyl-N-{(1R)-2-methyl-1-[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]propyl}amine;N²-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}glycinamide;ethylN-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-(2-ethoxy-2-oxoethyl)glycinate;4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(methoxymethyl)-1,3-thiazole;4-(2-(1-aminocyclopentyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol; orpharmaceutically acceptable salts or combinations thereof.
 5. Apharmaceutical composition comprising, as an active ingredient, at leastone of the compounds or pharmaceutically acceptable salts of claim
 4. 6.A method of treating disorders/pathologies selected fromneurodegenerative diseases, pain, or epilepsy comprising administering amedicament to a patient, wherein the medicament comprises one of thecompounds or pharmaceutically acceptable salts of claim
 4. 7. The methodof claim 6, wherein the disorders/pathologies treated areneurodegenerative diseases.
 8. The method of claim 7, wherein thecompound or pharmaceutically acceptable salt is4-[2-(1-aminocyclopentyl)-1,3-thiazol-4-yl)-2,6-di-tert-butylphenol orpharmaceutically acceptable salts thereof.
 9. The method of claim 6comprising treating pain.
 10. The method of claim 9, wherein thecompound or pharmaceutically acceptable salt is butyl2-[4-(4-aminophenyl)-1H-imidazol-2-yl)ethylcarbamate or pharmaceuticallyacceptable salts thereof